Mycophenolate Pharmacokinetics and Association with Response to Acute Graft-Versus-Host Disease Treatment from the Blood and Marrow Transplant Clinical Trials Network
03/2010
Journal Article
Authors:
Jacobson, P.;
Huang, J.;
Wu, J.;
Kim, M.;
Logan, B.;
Alousi, A.;
Grimley, M.;
Bolanos-Meade, J.;
Ho, V.;
Levine, J.;
Weisdorf, D.
Secondary:
Biol Blood Marrow Transplant
Volume:
16
Pagination:
421-429
URL:
http://www.ncbi.nlm.nih.gov/pubmed/19925875
Keywords:
Adrenal Cortex Hormones; Adult; Communicable Diseases; Gastrointestinal Tract; Glucuronides; Graft vs Host Disease; Immunosuppressive Agents; liver; Middle Aged; mycophenolate mofetil; Mycophenolic Acid; Survival Analysis
Abstract:
There are limited data as to the effectiveness of mycophenolate mofetil (MMF) plus high-dose corticosteroids for the treatment of acute graft-versus-host disease (aGVHD), and even less data regarding the pharmacokinetic disposition and exposure-response relationship of MMF in individuals with GVHD. MMF pharmacokinetics were studied in a multicenter Blood and Marrow Transplant Clinical Trials Network randomized phase II trial evaluating the effectiveness of MMF as one of 4 agents added to corticosteroids as treatment of aGVHD. Thirty-two of the patients randomized to receive MMF underwent pharmacokinetic sampling in weeks 1 and 2 were studied. Mean age was 41 +/- 13.6 years. Twenty one (65.6%), 5 (15.6%), 6 (18.8%) patients had a complete response (CR), partial response (PR) or lesser response by day 28, respectively. Twenty-five (78.1%), 2 (6.3%), 5 (15.6%) patients had a CR, PR, or other response by day 56 to treatment, respectively. Mycophenolic acid (MPA) pharmacokinetic measurements from weeks 1 and 2 did not correlate with CR at either day 28 or day 56 (P > .07); however, if the mean of weeks 1 and 2 total MPA troughs was >0.5 microg/mL or that of an unbound trough was >0.015 microg/mL, then a significantly greater proportion achieved CR + PR at days 28 and 56. CR + PR at day 28 was observed in 19 of 19 patients (100%) with a mean total trough >0.5 mg/mL, but in only 7 of 13 (54%) with a mean total trough < or =0.5 microg/mL (P = .002). Similarly, CR + PR at day 28 was seen in 15 of 15 patients (100%) with an unbound trough concentration >0.015 microg/mL, but in only 11 of 17 (65%) with an unbound trough concentration < or =0.015 microg/mL (P = .02). There was no association between the pharmacokinetic measures and risk of infection by day 90 or overall survival (OS) at day 180 postrandomization. About one-half of subjects did not achieve the favorable MPA total and unbound trough concentrations. The current practice of MMF 1 gm twice daily dosing provides low plasma concentrations in many patients. Higher doses may improve the efficacy of MMF as aGVHD therapy.
